Lung cancer represents one of the major public health problems worldwide. It has been estimated that between 1.3 and 2 million people died from lung cancer in the year 2000. The number of deaths caused by lung cancer exceeds those caused by the next three leading cancers together per year (breast, prostate and colorectal cancers). A decrease in mortality from lung cancer by improved diagnostic means would have an enormous impact on public health as well as reducing health care costs.
Ninety-nine percent of lung tumors are malignant, either primary or secondary. Non-Small Cell Lung Carcinoma (NSCLC) represents 80% of the bronchogenic carcinomas, which include Adenocarcinoma, SCC (Squamous Cell Carcinoma), LCC (Large Cell Carcinoma), and others. Small Cell Lung Cancer (SCLC), sometimes known as Oat Cell Carcinoma, comprises the rest of the cases. SCLC is the most aggressive type with a median survival of 2-4 months. Less common types include Sarcoma, Carcinosarcoma, Blastoma, Lymphoma, and Neuroendocrine tumors such as Carcinoids (both malignant and benign).
Half of patients seeking medical consultation do so when the disease has already advanced beyond surgical treatment. Since the lung parenchyma lacks nerve endings, tumors of the lung can become large before causing local symptoms such as coughing (75%), dyspnea (60%), pain (50%) and hemoptysis (30%). Fever, wheezing, stridor, hoarseness, SVC (Superior Vena Cava) syndrome, Homer syndrome, dysphagia, pleural effusion, and phrenic nerve paralysis may occur as well. Seventy percent of the patients have non-specific symptoms (such as anorexia, myalgia and weight loss), and a minority are asymptomatic. Some present with pneumonia due to bronchial obstruction, and some are diagnosed incidentally by a CXR (Chest X-Ray) assigned for another purpose.
Since pulmonary lesions are commonly encountered in clinical practice, differentiation of benign from malignant tissue remains a challenge for the radiologist. A broad variety of diagnostic techniques is available, with others being developed. Among these diagnostic techniques are the following:
i) CXR (Conventional Chest X-Ray) is the basic diagnostic tool. CXR may provide information regarding factors such as the size, shape, density and site of the lesion, apart from the existence of pleural effusions, alveolar or interstitial spread, collapse, lymphadenopathy, and rib metastases. An opacity is suspicious for malignancy if it has not calcified, has speculations, grows rapidly, or is >3 cm in diameter. There may also be hints about the histological type with Adenocarcinoma being peripheral, SCC central and large, and SCLC large, hilar, and with mediastinal lymphadenopathy. A lesion that has not grown in two years may be generally considered to be benign.ii) CT (Computed Tomography) is a preferred modality for lung cancer diagnosis and staging. The injection of a contrast agent or material helps differentiate between blood vessels and lymph nodes. CT can offer better evaluation of the tumor's borders, the tumor's relation to neighboring structures, and the involvement of lymph nodes, bones, liver and adrenals.
Technical modifications of CT include: low-dose helical CT (spiral CT), HRCT—high Resolution CT and phase-contrast CT. Spiral CT provides higher spatial resolution than a CXR, at the expense however, of greater radiation exposure. For example, in conventional CT the radiation exposure may be greater by 10-100 than that in a CXR, while spiral CT exposes the subject to only 10-20% the exposure of conventional CT. CT allows scanning of the whole lung during a single breath-hold of 8-25 seconds. In functional CT, enhancement obtained by the contrast material is usually greater in malignant tumors due to the rich vascularity typical of malignant tissue. Typically, non-enhancement means no malignancy, although some benign tissues do enhance.
Currently, due to the common availability of CT, particularly of fast multislice CT scanners, CT remains the imaging gold standard for lung diagnosis. Promising results concerning the use of dynamic contrast enhanced CT were recently presented, using calculations of vascular parameters based on density-time curves. Perfusion values of lung nodules obtained by CT were found to agree with those obtained by PET, and to correlate with VEGF (vascular endothelial growth factor) levels.
Tumor perfusion has been found to be dependent on tumor size and localization, but not on histology. Furthermore, perfusion CT disclosed blood supply from both pulmonary and/or bronchial vessels in some tumors. In these dynamic studies both the spatial and temporal resolution were high but the scanning was limited to small volumes and short time span in order to minimize radiation hazards.
CT detects lesions that are greater than 2 mm, of which 45% are neoplastic. CT is superior to CXR because CT provides staging, volumetric, and density data (higher enhancement and size being more characteristic of malignancy), and evaluation of the best method to obtain a biopsy, including needle localization for biopsy under VATS (Video Assisted Thoracoscopic Surgery). Advancement in SPN (solitary pulmonary nodule) evaluation by CT has been made by improvements in image processing and computer assistance, named CAD (Computer-Aided Diagnosis).
iii) MRI (Magnetic Resonance Imaging) differentiates between solid and vascular structures, even without contrast material. Most importantly, MRI uses relatively harmless radio waves and there is no exposure to ionizing radiation as in CT. Due to longer acquisition time, patient movement is more detrimental.
The potential role of dynamic contrast enhanced (“DCE”) MRI based evaluation of solitary pulmonary nodules was first described by Hittmair et al. The maximum enhancement and the initial velocity of contrast uptake were assessed and correlated with pathohistological findings. Malignant neoplastic SPNs enhanced stronger and faster than benign neoplastic SPNs.
More recently, additional DCE-MRI studies of SPNs confirmed the early results (Ohno Y, Hatabu H, Takenaka D, Adachi S, Kono M, Sugimura K. Solitary Pulmonary Nodules: Potential Role of Dynamic MR Imaging in Management Initial Experience Radiology, 2002 Aug; 224(2):503-11. See also, Fujimoto K, Abe T, Muller N L, Terasaki H, Kato S, Sadohara J, Kono R, Edamitsu O, Ishitake T, Hayashi A, Rikimaru T, Hayabuchi N., Small Peripheral Pulmonary Carcinomas Evaluated with Dynamic MR Imaging: Correlation with Tumor Vascularity and Prognosis, Radiology. 2003 Jun; 227(3): 786-93, Epub 2003 Apr. 24. Schaefer J F, Vollmar J, Schick F, Vonthein R, Seemann M D, Aebert H, Dierkesmann R, Friedel G, Claussen C. D. Solitary Pulmonary Nodules: Dynamic Contrast-Enhanced MR Imaging—Perfusion Differences in Malignant and Benign Lesions. Radiology. 2004 Aug; 232(2):544-53. Epub 2004 Jun. 23). The parameters measured were peak enhancement and slope of enhancement and in some studies wash-out ratio and time to maximum were added as well. In Fujimoto's study, the DCE-MRI parameters correlated with tumor vascularity suggesting a potential use for this method to predict prognosis.
The response of the vascular physiology to treatment of lung cancer was also assessed by DCE MRI (Hunter G. J., Hamberg L. M., Choi N, Jain R. K., McCloud T, Fischman A. J., Dynamic T1-Weighted Magnetic Resonance Imaging and Positron Emission Tomography In Patients with Lung Cancer: Correlating Vascular Physiology with Glucose Metabolism, Clin. Cancer Res. 1998 Apr; 4 (4):949-55).
The mean capillary permeability and surface area product (PS) in tumors was 0.0015+/−0.0002 s(−1) (n=13) before, 0.0023+/−0.0003 s(−1) (n=3, P=0.053) midway through, and 0.00075+/−0.0002 s(−1) (n=5, P<0.03) 2 weeks after treatment. Values for the extracellular contrast distribution space were 0.321+/−0.03 before, 0.289+/−0.02 midway through, and 0.195+/−0.02 (P<0.01) 2 weeks after therapy. The glucose metabolic rate was significantly correlated with the PS product (P<0.01) but not with the extracellular contrast distribution space.
iv) PET (Positron Emission Tomography) using 18-fluorodeoxyglucose depicts increased glucose metabolism in tumor cells. This served to evaluate the primary tumor as well as regional lymph nodes and distant metastases.
Percutaneous needle biopsy, flexible fiberoptic bronchoscopy as well as surgical exploration offer additional diagnostic tools. However, they are characterized by inherent invasiveness. Recent developments include exhalation analysis of certain volatile organic compounds, cytological sputum analysis, immunostaining for hnRNP, A2/B1 or PGP9.5, and polymerase chain reaction-based assays for detecting tumor-specific mutations. Despite the various diagnostic modalities, 10-20% of patients undergo thoracotomy without prior pathologic diagnosis. The exact treatment regimen depends on precise histological data before treatment and after excision.
Early detection leads to better prognosis. For example, in stage I the survival is 60-70% and in stage Ia even higher. Unfortunately, only 15% of the cases are diagnosed at an early stage (I and II) when the tumor is well localized, so the overall survival has not risen lately. The one-year survival rate has increased from 32% in 1973 to 41% in 1994. However, the overall five-year survival rate is only 14%. Concerning lung metastases, the prognosis depends on the type of primary tumor and its biological behavior. For some carcinomas and sarcomas, the five-year survival after lung metastases excision is 25-45%.
The best chance of survival is expected when lung cancer presents incidentally on a CXR as a “coin lesion”, or SPN, which is single, peripheral and asymptomatic. The SPN is defined as an abnormal round/oval density of diameter <=3 cm, surrounded by lung parenchyma and lacking cavitations or pulmonary infiltrates. There could be eccentric flecks of calcifications, but not broad or concentric ring calcifications. Approximately 80% of the coin lesions are malignant in patients of age >50 years. Only when the lesion has been known to exist for at least two years without enlarging and with a “benign” calcification pattern, could histological diagnosis be delayed.
Only about half of lesions suspicious enough to undergo an open biopsy turn out to be malignant. This brings about not only needless morbidity and mortality. The hospitalization costs of such a patient in the US are about $25,000. When a SPN is detected, it represents primary lung cancer in most breast cancer patients, and a metastasis in most melanoma patients. For cancer of the gastrointestinal tract the odds for both options are equal. Follow-up of a SPN is usually dependent upon the lesion's diameter:
1. <5 mm: HRCT after 3, 6, 12 & 24 months. Consider biopsy if enlarges. 1% malignancy.
2. 5-10 mm: as above, but 25-30% malignancy.
>10 mm: consider biopsy. 30-80% malignancy.
No fixed relationship exists between the size of the nodule and its biological behavior. It is possible that most patients already have metastases at the time of diagnosis, which the routine diagnostic tools do not always detect. This hypothesis is supported by clinical studies in which lymph nodes that appeared normal were found to contain metastases when evaluated by immunohistochemical staining or PCR (polymerase chain reaction).
There is general agreement among the various health organizations in the U.S., that the screening programs customary until recently (CXR and sputum cytology), have not contributed significantly to decrease the death rate. This is not true for the next three most common cancers: breast, prostate and colorectal, for which the death rate has decreased by 10-15% in the past 2 decades. It should also be noted, that in the Johns Hopkins Lung Project from the 70's, screening tests were negative in half of the patients that developed lung cancer, and became symptomatic before the next scheduled screening examination. A possible explanation was that some of the cases are so aggressive, that even strict follow-up and early detection will not increase survival. Actually, screening is intended mainly or NSCLC (75-80% of the cases), since SCLC is usually widely disseminated at presentation.